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Review
. 2015 May 13:6:228.
doi: 10.3389/fimmu.2015.00228. eCollection 2015.

Mechanisms of autoantibody production in systemic lupus erythematosus

Shuhong Han  1 , Haoyang Zhuang  1 , Stepan Shumyak  1 , Lijun Yang  2 , Westley H Reeves  1
Affiliations
Review

Mechanisms of autoantibody production in systemic lupus erythematosus

Shuhong Han et al. Front Immunol. .

Abstract

Autoantibodies against a panoply of self-antigens are seen in systemic lupus erythematosus, but only a few (anti-Sm/RNP, anti-Ro/La, anti-dsDNA) are common. The common lupus autoantigens are nucleic acid complexes and levels of autoantibodies can be extraordinarily high. We explore why that is the case. Lupus is associated with impaired central or peripheral B-cell tolerance and increased circulating autoreactive B cells. However, terminal differentiation is necessary for autoantibody production. Nucleic acid components of the major lupus autoantigens are immunostimulatory ligands for toll-like receptor (TLR)7 or TLR9 that promote plasma cell differentiation. We show that the levels of autoantibodies against the U1A protein (part of a ribonucleoprotein) are markedly higher than autoantibodies against other antigens, including dsDNA and the non-nucleic acid-associated autoantigens insulin and thyroglobulin. In addition to driving autoantibody production, TLR7 engagement is likely to contribute to the pathogenesis of inflammatory disease in lupus.

Keywords: B cells; TLR7; autoantibodies; immune tolerance; innate immunity; lupus erythematosus; systemic.

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Figures

Figure 1
Figure 1
Serum autoantibodies in SLE. Levels of serum IgG anti-U1A, dsDNA, insulin, and thyroglobulin autoantibodies were tested by ELISA in 23 consecutive SLE patients and 13 controls. SLE was classified using the ACR criteria. Healthy controls age and gender-matched had no history of systemic autoimmune disease. These studies were reviewed and approved by the University of Florida Institutional Review Board. (A) Antigens were coated on plastic wells at 0.8 μg/ml and sera were diluted 1:500 for screening. (B) ELISA titration curves (serial twofold dilutions) for the four sera most strongly reactive with each antigen. Patient ID number is shown in the key. (C) Frequencies of anti-dsDNA, anti-RNA-protein (rNP, anti-Sm, RNP, Ro/SS-A, and La/SS-B) autoantibodies detected by commercial ELISAs in a cohort of 106 SLE patients. Only 6% of the sera were unreactive with both dsDNA and the ribonucleoprotein autoantigens.
Figure 2
Figure 2
Proposed model of autoantibody generation in SLE. SLE is associated with genetic abnormalities that impair central or peripheral B-cell tolerance. In the presence of T-cell help, autoreactive B cells that escape censoring may develop into IgG-producing memory B cells. However, these cells can circulate without producing autoantibodies. Following subsequent antigen exposure, the memory cells enhance their expression of BLIMP-1 and develop into autoantibody-secreting plasma cells. In the case standard autoantigens, such as insulin, which engage only the B-cell receptor, the stimulus to undergo terminal (plasma cell) differentiation is weaker than in the case of RNA-associated autoantigens, such as U1A, which can activate terminal B-cell differentiation via both the B-cell receptor and TLR7. This may explain why levels of anti-U1A (RNP) autoantibodies are markedly higher than anti-insulin autoantibody levels.
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